The present invention relates generally to magnetic resonance imaging (xe2x80x9cMRIxe2x80x9d) and spectroscopy methods, and more particularly to the use of hyperpolarized 129Xe in MRI and spectroscopy.
MRI using hyperpolarized noble gases has been demonstrated as a viable imaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert et al. The contents of this patent are hereby incorporated by reference as if recited in full herein. Albert et al. proposed several techniques of introducing the hyperpolarized gas (either alone or in combination with another substance) to a subject, such as via direct injection, intravenous injection, and inhalation. See also Biological magnetic resonance imaging using laser-polarized 129Xe, 370 Nature, pp. 199-201 (Jul. 21, 1994). Other researchers have since obtained relatively high-quality images of the lung using pulmonary ventilation of the lung with both hyperpolarized 3He and 129Xe. See J. R. MacFall, H. C. Charles, R. D. Black, H. Middleton, J. Swartz, B. Saam, B. Driehuys, C. Erickson, W. Happer, G. Cates, G. A. Johnson, and C. E. Ravin, xe2x80x9cHuman lung air spaces: Potential for MR imaging with hyperpolarized He-3,xe2x80x9d Radiology 200, 553-558 (1996); and Mugler et al., MR Imaging and spectroscopy using hyperpolarized 129Xe gas: Preliminary human results, 37 Mag. Res. Med., pp. 809-815 (1997). See also E. E. de Lange, J. P. Mugler, J. R. Brookeman, J. Knight-Scott, J. Truwit, C. D. Teates, T. M. Daniel, P. L. Bogorad, and G. D. Cates, xe2x80x9cLung Airspaces: MR Imaging Evaluation with Hyperpolarized Helium-3 Gas, xe2x80x9d Radiology 210, 851-857(1999); L. F. Donnelly, J. R. MacFall, H. P. McAdams, J. M. Majure, J. Smith, D. P. Frush, P. Bogorad, H. C. Charles, and C. E. Ravin, xe2x80x9cCystic Fibrosis: Combined Hyperpolarized 3He-enhanced and Conventional Proton MR Imaging in the Lungxe2x80x94Preliminary Observations,xe2x80x9d Radiology 212 (September 1999), 885-889 (1999); H. P. McAdams, S. M. Palmer, L. F. Donnelly, H. C. Charles, V. F. Tapson, and J. R. MacFall, xe2x80x9cHyperpolarized 3He-Enhanced MR Imaging of Lung Transplant Recipients: Preliminary Results,xe2x80x9d AJR 173, 955-959 (1999).
In addition, due to the high solubility of 129Xe in blood and tissues, vascular and tissue imaging using inhaled hyperpolarized 129Xe has also been proposed. Generally described, during inhalation delivery, a quantity of hyperpolarized 129Xe is inhaled by a subject (a subject breathes in the 129Xe gas) and the subject then holds his or her breath for a short period of time, i.e., a xe2x80x9cbreath-holdxe2x80x9d delivery. This inhaled 129Xe gas volume then exits the lung space and is generally taken up by the pulmonary vessels and associated blood or pulmonary vasculature at a rate of approximately 0.3% per second. For example, for an inhaled quantity of about 1 liter of hyperpolarized 129Xe, an estimated uptake is about 3 cubic centimeters per second or a total quantity of about 40 cubic centimeters of 129Xe over about a 15 second breath-hold period. Accordingly, it has been noted that such uptake can be used to generate images of pulmonary vasculature or even organ systems more distant from the lungs. See co-pending and co-assigned U.S. patent application Ser. No. 09/271,476 to Driehuys et al, entitled Methods for Imaging Pulmonary and Cardiac Vasculature and Evaluating Blood Flow Using Dissolved Polarized 129Xe. Although primarily directed to inhalation delivery, this application also proposes injection of 129Xe to replace conventional radioactive tracers in perfusion imaging methods. The contents of this application are hereby incorporated by reference as if recited in full herein.
Many researchers are also interested in the possibility of using inhaled 129Xe for imaging white matter perfusion in the brain, renal perfusion, and the like. While the inhaled delivery 129Xe methods are suitable, and indeed, preferable, for many MRI applications for several reasons, such as the non-invasive characteristics attendant with such a delivery to a human subject, it may not be the most efficient method to deliver a sufficiently large dose to more distant (away from the pulmonary vasculature which is proximate to the lungs) target areas of interest. In addition, due to the dilution of the inhaled 129Xe along the perfusion delivery path, relatively large quantities of the hyperpolarized 129Xe are typically inhaled in order to deliver a small fraction of the gas to the more distal target sites or organ systems. For example, the brain typically receives only about 13% of the total blood flow in the human body. Thus, the estimated 40 cubic centimeter quantity of hyperpolarized 129Xe taken up into the pulmonary vessels from the 1-liter inhalation dose can be reduced to only about 5 cubic centimeters by the time it reaches the brain.
Further, the hyperpolarized state of the gas is sensitive and can decay relatively quickly due to a number of relaxation mechanisms. Indeed, the relaxation time (generally represented by a decay constant xe2x80x9cT1xe2x80x9d) of the 129Xe in the blood, absent other external depolarizing factors, is estimated at T1=4.0 seconds for venous blood and T1=6.4s for arterial blood at a magnetic field strength of about 1.5 Tesla. See Wolber et al., Spin-lattice relaxation of laser-polarized xenon in human blood, 96 Proc. Natl. Acad. Sci. USA, pp. 3664-3669 (March 1999). (The more oxygenated arterial blood provides increased polarization life over the relatively de-oxygenated venous blood). Therefore, for about a 5 second transit time (the time estimate for the uptaken hyperpolarized 129Xe to travel to the brain from the pulmonary vessels), the 129Xe polarization is reduced to about 37% of its original value. In addition, the relaxation time of the polarized 129Xe in the lung itself is typically about 20-25 seconds due to the presence of paramagnetic oxygen. Accordingly, 129Xe taken up in the latter portion of the breath-hold cycle can decay to have only about 50% of the starting polarization (the polarization level at the initial portion of the breath hold cycle). Thus, generally stated, the average polarization of 129Xe entering the pulmonary blood can be estimated to be at about 75% of the starting inhaled polarization value. Taking these effects into account, the delivery to the brain of the inhaled 129Xe can be estimated as about 1.4 cubic centimeters of the inhaled one-liter dose of 129Xe polarized to the same level as the inhaled gas (0.75xc3x970.37xc3x975 cc""s). This dilution reduces delivery efficiency, i.e., for remote target areas (such as the brain), the quantity of delivered 129Xe is typically severely reduced to only about 0.14% of the inhaled 129Xe. Nonetheless, at least one researcher has made coarse images of 129Xe in rat brains, but this inhalation administration delivery required large quantities of 129Xe to be inhaled over a relatively long period of time. See Swanson et al., Brain MRI with laser-polarized xenon in human blood, 38 Mag. Reson. Med., pp. 695-698 (1997). Unfortunately, the extended inhalation time period and/or associated large quantity dosage of the gas may not be desirable for certain clinical applications.
In an alternative delivery mode, Bifone et al. proposes the use of injectable formulations to deliver hyperpolarized 129Xe to regions of interest. Bifone et al., NMR of laser polarized xenon in human blood, 93 Proc. Natl. Acad. Sci. USA No. 23, pp. 12932-12936 (1996). Albert et al., supra, also describes such formulations. As described by Bifone et al., the injectable formulation consists of a biocompatible fluid in which hyperpolarized 129Xe is dissolved. Such formulations can then be injected intravenously to deliver hyperpolarized 129Xe. For fluid injection, the formulation is described as preferably formed such that the biocompatible fluid has a high solubility for xenon while also providing a relatively long 129Xe relaxation time. Examples of particular suggested biocompatible fluids include saline, lipid emulsions, and perfluorocarbon emulsions. Several researchers have shown images of fluid injectable formulations. For example, Goodson et al. have shown images of 129Xe dissolved in saline and injected into the hind leg of a rat. Goodson et al., In vivo NMR and MRI Using Injection Delivery of Laser-Polarized Xenon, 94 Proc. Natl. Acad. Sci. USA, pp. 14725-14729 (1997). Moeller et al. have also recently demonstrated venous angiography with hyperpolarized 129Xe dissolved in Intralipid(copyright) solution. Moeller et. al., Magnetic Resonance Angiography with Hyperpolarized 129Xe Dissolved in Lipid Emulsion, 41 Mag. Res. Med. No. 5, pp. 1058-1064 (1999). The Intralipid(copyright) formulation purportedly has a xenon-Otswald solubility of about 0.6 and a 129Xe relaxation time of 25 seconds in a magnetic field strength of 2.0 Tesla. In addition, Wolber et al, have also recently demonstrated PFOB (perfluorooctyl bromide) emulsions which allegedly have increased transverse relaxation times and have purportedly provided improved imaging results. Wolber et al., Perfluorocarbon Emulsions as Intravenous Delivery Media for Hyperpolarized Xenon, 41 Mag. Res. Med., pp. 442-449 (1999). In yet another injection technique, Chawla et al., have proposed the use of hyperpolarized 3He microbubbles suspended in a hexabrix solution to perform angiography on rats. Chawla et al., In Vivo Magnetic Resonance Vascular Imaging Using Laser-Polarized 3He Microbubbles, 95 Proc. Natl. Acad. Sci. USA, pp. 10832-10835 (1998).
Unfortunately, many injectable formulations can be unduly susceptible to handling and processing variables which can negatively impact the injectable formulation""s commercial viability and/or clinical application. For example, the relatively short (and potentially magnetic-field dependent) relaxation time of the 129Xe in the injectable solutions can require that the 129Xe gas be dissolved into the biocompatible fluid relatively quickly and then subsequently rapidly injected to reduce the polarization loss of the formulation prior to injection. In addition, it may be difficult to predict the dissolution efficiency in a manner which can provide a reliable xenon dissolution concentration. Unreliable concentrations can, unfortunately, yield widely varying signal intensities, dose to dose. Further, because of the typically relatively quick decay associated with these formulations, a careful measurement of the final 129Xe polarization just prior to injection to determine the post dissolution polarization may not be possible. Still further, because the 129Xe is dissolved in a biocompatible fluid, sensitivity to the local in vivo environment such as blood oxygenation, tissue type, and the like, may be muted, reduced, or even non-existent. The use of such fluids or carrier agents to deliver 129Xe to selected tissues or organs can also be difficult because of the high solubility of 129Xe in the fluid compared to the tissues (its preferred affinity being to remain in the fluid rather than to migrate into the selected or targeted tissues).
In view of the foregoing, and despite the present efforts, there continues to be a need to improve the methods, products, and systems used to deliver hyperpolarized 129Xe gas to a target in vivo imaging region of interest.
It is therefore an object of the present invention to formulate and deliver 129Xe in vivo in a manner which allows for high-quality mammalian tissue, organ, vascular, and/or angiographic MRI images using hyperpolarized gaseous 129Xe.
It is another object of the present invention to provide a method of using reduced quantities of hyperpolarized gas while providing increased MRI image signal resolution.
It is an additional object of the present invention to provide methods for obtaining improved quality NMR signals and/or MRI images of both the arterial and venous portions of the human vasculature and/or organs and/or systems using hyperpolarized 129Xe.
It is a further object of the present invention to provide appropriate (bolus) sized containers and associated delivery systems, apparatus, and methods which can reduce the depolarization of the hyperpolarized 129Xe gas prior to and during delivery and can, thus, yield a clinically useful T1.
It is another object of the present invention to introduce a sufficient quantity of hyperpolarized 129Xe gas into the vasculature in a minimally intrusive manner to obtain MR spectroscopic signal and/or in vivo images.
It is yet another object of the present invention to facilitate the dissipation or dispersion of bubbles which may be injected into a subject.
It is an additional object of the present invention to provide imaging methods which may be able to screen for the presence of pulmonary emboli.
It is still another object of the invention to formulate 129Xe as a pharmaceutical grade injectable formulation which can be monitored for polarization efficacy just prior to use with reduced decaying effect thereon.
It is another object of the present invention to provide NMR-based diagnostic capability of vasculature (arterial and/or venous or organ) circulation related defects or emboli in a minimally or non-invasive and effective manner.
It is yet another object of the present invention to provide a diagnostic tool for the evaluation of pharmaceutical effectiveness on drugs directed to target regions or functions.
It is an additional object of the present invention to provide in vivo diagnostic information regarding the cancerous condition of a solid mass.
It is another object of the present invention to prepare gas contacting surfaces and containers in a manner which reduces the amount of depolarizing oxygen therein while also employing purge gas which is suitable for injection.
It is still an additional object of the present invention to provide a way to optimize capillary length for improved polarization life in containers configured to hold polarized noble gases such as 129Xe and/or 3He.
These and other objects of the present invention are provided by directly injecting in vivo a predetermined quantity of hyperpolarized 129Xe in gaseous phase to obtain MR based spectroscopic signal or images regarding a target site in the mammalian vasculature (or target organ, tissue, or region). The present invention also includes delivery and dispensing methods, systems, and product formulations, as well as administration rates which may correspond to the use or injection site. In addition, the present invention provides polarization monitoring of the hyperpolarized gaseous 129Xe which is formulated for direct injection in vivo into the vasculature for MR imaging and spectroscopic analysis.
In particular, a first aspect of the present invention is directed toward the detection or screening for the presence of a pulmonary embolism. The method includes the step of positioning a subject having a pulmonary region and a blood circulation path including veins and arteries in a NMR system. The subject""s pulmonary region has pulmonary veins and pulmonary arteries and associated vasculature defining a pulmonary portion of the circulation path. A quantity of polarized gaseous 129Xe is injected directly into at least one vein of the subject. NMR signal data associated with the polarized 129Xe in the pulmonary region of the subject is obtained. The signal data includes information corresponding to the polarized gas introduced in the injecting step. An MRI image is generated having spatially coded visual representation of the NMR signal data. The presence of at least one condition of blockage, restriction, abnormality, and substantially unobstructed free passage of the pulmonary circulation path is identified.
In one embodiment, the quantity of venous injected gaseous 129Xe is less than about 100 cubic centimeters while quantity of arterial injected gaseous 129Xe is less than about 14-20 cc""s.
In another embodiment, in order facilitate bubble dissipation which may be associated with the injection of the 129Xe gas within the subject, a quantity of liquid surfactant can be introduced in vivo temporally and spatially proximate to the gas injection (or concurrently at a location proximate to the gas injection) site. The injection pressure and/or the rate of injection can also be substantially controlled to thereby control the delivery rate of the polarized gaseous 129Xe into the injection site typically to about 1-3 cc/s or less for venous entry. The gas injection may be performed in a manner which reduces the bubble size associated with the injected gas to preferably to less than about 5-10 xcexcm in diameter for certain embodiments (particularly for arterial injections) and less than about 75-150 xcexcm in diameter for venous injections.
In one embodiment, a second quantity of a polarized gas is introduced to a subject during the same imaging session. That is, the first quantity is injected and an associated first image or signal acquisition can be obtained, and a second delivery and a second data or signal acquisition or image associated with the second quantity can be obtained. For example, the second delivery can be via inhalation of a hyperpolarized gas (either 3He or 129Xe, although for system equipment and coil tuning reasons, 129Xe gas is preferred) and the signal/image can be obtained after a short lapsed time period from the first signal/image (a time sufficient to clear traces of the polarized injected xenon from the target area). Additionally, or alternatively, the inhalation dose can be delivered prior to the injection of the polarized gas. Alternatively, concurrent delivery of the injection and inhalation doses may be used. It is anticipated that this may help with co-registration between the two images and may reduce image artifacts. Of course, the second delivery can be another injectable dose of 129Xe gas, or an injection of a hyperpolarized gas product in liquid form (such as dissolved in a carrier liquid).
Another aspect of the present invention is directed toward a method of obtaining MRI-based medical images. The method includes injecting directly into an injection site of a subject a first quantity of polarized 129Xe in gaseous form and delivering a second quantity of polarized gas product to the subject within the same imaging session. The second delivery can be performed in a number of ways and with a number of polarized noble gas product formulations. For example, inhalation of a polarized noble gas mixture (such as described for the embodiment above) or another injection (either of the 129Xe gas directly or of a polarized noble gas product otherwise formulated such as in a carrier or liquid based injection formulation) at a point in time which is proximate to the injecting step. The second quantity is larger than the first (injected) quantity. An MRI image is then generated corresponding to the signal data acquisition obtained via NMR excitation of the first and second quantities of polarized gas introduced in said injecting and delivering steps.
In certain embodiments, the injecting step injection site is a site associated with the venous vasculature (such as a vein). In one embodiment, the delivering step is carried out by administering two separate polarized gas based doses. That is, the delivery step may be performed by injecting to second site in an artery and by inhaling a quantity of hyperpolarized gas. The second site or arterial injection quantity can be in fluid or gas formulation. Thus, the inhalation based delivering step introduces the polarized gas via inhalation and the inhaled gas is subsequently directed into pulmonary arterial vasculature via perfusion uptake.
In another embodiment, the NMR signal data associated with both the injecting and delivering steps is processed in a manner which distinguishes NMR signal information corresponding to gas versus dissolved gas signal information in the MRI image generating step. Alternatively, the MRI image-generating step is performed at a low magnetic field strength, and the NMR signal data is processed in a manner which combines or does not substantially distinguish between NMR signal data associated with excitation of the hyperpolarized gas whether in the gas phase or the dissolved phase (the peaks associated with the polarized gas in the red blood cells and plasma in the blood overlap).
An additional aspect of the present invention is directed to a method of obtaining diagnostic images of the cranial region. The method includes the steps of injecting less than about 5 cc""s (preferably about 1-2 cc""s) of 129Xe polarized gas into an injection site in a carotid artery and dissolving the polarized 129Xe gas into the vasculature proximate to the injection site. An NMR image is generated having signal intensity associated with the NMR excitation of the dissolved 129Xe. The signal can be associated with the 129Xe in one or more of the blood, grey matter, CSP, or white matter (to provide information corresponding to white matter perfusion typical of desired neurological assessments). The excitation or response signal can be processed in a manner which allows the correlation to a particular region of interest, such as, for example, highlighting differences in chemical shift, T2*, T1, and the like as will be appreciated by one of skill in the art. The method can include, inter alia, the step of introducing, in vivo, a surfactant to facilitate bubble dissipation proximate to the injection site
In one embodiment, the injecting step is performed at a (controlled) rate and/or pressure sufficient to facilitate the dissolution of the gas in the vasculature proximate to the injection site and/or in a manner which reduces the size of bubbles introduced therewith corresponding to the selected injection site (preferably to form smaller size bubbles and smaller quantities of gas for arterial injections). An injection head with multiple orifices sized with a diameter of between about 1 nm-50 xcexcm, and typically between about 0.01-10 xcexcm can be used and the gas may be mixed in situ with an emulsifier prior to delivery to facilitate a fine dispersion of gas into the body of the subject.
Another aspect of the present invention is directed toward a method of obtaining an MR image or NMR spectral data. The method includes injecting less than about 100 cc""s of hyperpolarized gas in vivo into an injection site associated with the vasculature of a mammalian subject. An NMR image or spectral data is then generated corresponding to the injected quantity of hyperpolarized 129Xe gas.
In one embodiment the method includes the step of administering the injection such that it remains substantially undissolved within the bloodstream for a period of time and such that it exhibits a T1 in the bloodstream of at least eight seconds. Alternatively, the method can administer the injection such that is employs an introduction rate selected so that the gas is dissolved (at least partially) into the vasculature proximate to the injection site and/or to reduce the size of bubbles associated with the injection.
In certain embodiments, the injection is performed by injecting the hyperpolarized 129Xe into at least one predetermined injection site such as in an arm, leg, or at other externally accessible or viable injection locations. For example, the injection site can be chosen from the group consisting of a carotid artery, a pulmonary artery, a renal artery, a hepatic artery, and a renal artery or the group consisting of a vein located in the arm (such as the central vein or peripheral vein), a jugular vein, a pulmonary vein, a hepatic vein, and a renal vein. In another preferred embodiment, the injecting step is performed by injecting the hyperpolarized 129Xe into at least two different injection sites, preferably the injection sites corresponding to a vein or artery which is externally accessible via injection of an IV or syringe needle such as in an arm, leg, or at other torso or other feasible locations.
The injection dose can be contained in a single-dose sized container. For arterial injections, the dose container can be sized and configured to hold less than about 14-20 cc""s of polarized 129Xe gas therein. For venous injections, the dose container can be sized and configured to hold less than about 100 cc""s of polarized 129Xe gas therein. The container can be a syringe configured with a primary body with a wall having outer and inner surfaces, and the inner surface is formed from a material which reduces contact induced polarization decay associated therewith. Preferably, the syringe body is operably associated with a capillary stem and valve to control the exit of gas from the syringe. The syringe body can also include an NMR excitation coil mounted thereon. For delivery, it is preferred that a catheter is positioned in a subject at the desired injection site (corresponding to the desired target image region in the subject). The catheter can include or be operably associated with a frit or needle which is formed or coated with a polarization friendly material (such as a gold plated or aluminum needle). The frit or needle may also be configured and sized to reduce the bubble size to at or below about a 10 micron diameter at injection. This reduced bubble size may be particularly suitable for arterial injection sites.
In certain embodiments, an injection system for administering polarized gas to a subject can include (a) a polarized noble gas supply; (b) a catheter configured and sized for intravenous or intrarterial placement in a subject in fluid communication with the supply of polarized noble gas; and (c) an injection head positioned in a distal portion of the catheter. The injection head can comprise multiple orifices which are configured so that, in operation, hyperpolarized gas flows therethrough and out of the catheter into the subject. The orifices can be sized with a width which is between about 1 nm-50 xcexcm, and typically between about 0.01-10 xcexcm.
In certain embodiments, the system can include an additive source (such as an emulsifier source) and a mixing chamber positioned intermediate the orifices and the additive or emulsifier and polarized gas sources to mix the hyperpolarized gas and the additive or emulsifier prior to expulsion from the injector head orifices (typically it is mixed in situ as the gas flows away from the gas source toward the exit orifice(s) in the injection head). The system may also include a heating or cooling means to promote the generation of a fine dispersion of gas mixture from the injection head (which typically resides in an IV inserted into the body).
In preparing the syringe, catheter, injection system, and/or conduit associated therewith for use according to the present invention, CO2 can be employed as a purge gas to prepare the container and reduce the likelihood of introducing nitrogen via injection into a subject (potentially leaving residual or traces of CO2 rather than nitrogen which has been conventionally used to prepare the polarized gas containers). As such, the injectable 129Xe may include small quantities or traces of CO2 therewith.
The system may include a resilient dose bag having external walls which are responsive to the application of pressure thereagainst and a quantity of hyperpolarized gas held in the dose bag along with an inflatable bladder which is sized and configured to receive at least a portion of the dose bag therein. In operation, the inflatable bladder is inflated to press against the dose bag external walls to thereby expel a quantity of the hyperpolarized gas from the dose bag.
In one embodiment, the present invention is configured to employ a dual path hyperpolarized gas product delivery system. For a manual presentation and delivery, a technician can deliver the 129Xe (inject) and then trigger a switch in the MRI unit indicating that the delivery is complete. The MRI unit, in response to activation of the switch, can initiate the imaging procedure such that it commences within the required polarization life at the target-imaging region. The MRI unit can also have a timer operably associated therewith which can alert the technician when it is acceptable to deliver the inhalation dose. The inhalation dose can be an optional delivery which is withheld if no reasonable indicia of perfusion deficits are indicated by NMR signal obtained based on the injected dose. Of course, the injection dose and the inhalation dose order can be reversed, wherein the injection dose is administered second. In addition, automated delivery and sequencing methods can also be employed as will be appreciated by one of skill in the art.
For concurrent delivery, the system can include a user audible and/or visual alert which is responsive to one or more of the dispensing systems (it is activated when a gas or liquid polarized product commences delivery at an IV or inhalation or other administration) that allows the dispensing of more than one dose/path of gas (such as the inhaled and injected gas) to be timed or substantially concurrently (or at a predetermined or desired interval) administered. This can facilitate the effective delivery and initiation of imaging sequences which can be important due to the limited polarization life of the polarized gas product in the blood.
An additional aspect of the present invention is a method of evaluating the efficacy of targeted drug therapy, comprising the steps of delivering a quantity of a predetermined gene treatment preparation or pharmaceutical drug in vivo into a mammalian subject having a target site and a treatment condition; injecting a predetermined quantity of gaseous phase hyperpolarized 129Xe in vivo into a mammalian subject such that the hyperpolarized gas is delivered to the target site in gaseous or dissolved form; generating a NMR image or spectroscopic signal of the target site associated with the injected hyperpolarized 129Xe gas; and evaluating the NMR image or spectroscopic signal to evaluate the efficacy of the gene treatment or drug on the treatment condition administered in the delivering step.
In one embodiment, the method further comprises the step of acquiring at least two sets of data, the data representing two temporally spaced apart points in time, to evaluate if the treatment condition is influenced by the drug or gene therapy introduced in the delivering step. Of course, the evaluation may be performed without regard to toxicity and/or survival if done in connection with animal research.
Another aspect of the invention is a method of determining the presence of cancerous tissue, comprising the steps of delivering a quantity of a pharmaceutical drug in vivo into a mammalian subject having a target site associated with a suspect mass or tissue abnormality; injecting a quantity of gaseous hyperpolarized 129Xe in vivo into a mammalian subject such that the hyperpolarized gas is delivered to the target site; generating a NMR image or spectroscopic signal of the target site corresponding to the injected hyperpolarized 129Xe gas; and evaluating the NMR image or signal for the presence or absence of signature patterns in the generated image or signal associated with the presence or absence of cancer.
An additional aspect of the present invention is an injectable 129Xe gas product, the 129Xe gas product formulated as a sterile non-toxic hyperpolarized gas formulation which consists essentially of isotopically enriched 129Xe in gaseous phase which is injected in vivo in a quantity of less than about 20-100 cubic centimeters.
Similarly, another aspect of the present invention is an injectable 129Xe gas pharmaceutical grade product, the product formulated as a sterile non-toxic product which consists essentially of 129Xe in gaseous phase and traces of CO2, wherein the injectable gas product is configured to be dispensed in vivo.
The present invention is advantageous because relatively small quantities of (preferably isotopically enriched) hyperpolarized 129Xe gas with relatively predictable or known polarization levels can provide high-quality MRI images or spectroscopy data with clinically useful signal resolution for in vivo tissue and/or vasculature. Indeed, in one preferred embodiment, the pulmonary embolism detection method can be performed as a relatively quick screening method typically with high quality diagnostic information about the circulatory path, such as in under about 15 minutes. In this embodiment, it is preferred that both an inhalation (ventilation) and injection delivery of hyperpolarized gas are used to generate a combined (dual) introduction path. That is, inhalation can provide a first order image or ventilation image of the lungs. However, the gas migrates into the vasculature and/or is uptaken by the blood stream and, thus, is introduced into a pulmonary vein(s). This uptake can provide MRI or NMR venous spectra/information of the venous side of the circulatory system. In contrast, the injection into a venous pathway can yield NMR arterial signal information (generally described, the 129Xe gas injected in a vein travels/flows to the right side of the heart and then into a pulmonary artery). Therefore, the dual introduction path can provide a more complete image/signal of both the arterial and venous side of the pulmonary vasculature. Conveniently, by using polarized 129Xe gas both as the inhalation and injection NMR medium, the pulmonary embolism screening method can use the same NMR chest coil for the excitation and detection of the 129Xe signals associated with the inhaled/perfusion dose and the injected dose.
Of course, direct injection of 129Xe polarized gas to a particular target site such as a tumor can allow for additional diagnostic information over many conventional procedures. For example, in vivo cancerous tumors can be characterized by the presence of increased random blood vessel growth (a condition known as angiogenisis). This is in contrast to benign cysts. Taking advantage of this characteristic and the NMR signal information available using direct 129Xe polarized gas injection, the present invention can analyze in vivo a target in an organ such as a tumor in a breast. For example, a needle can be inserted or injected to the suspect region in the breast via conventional MR guided needle placement and 129Xe can be released thereat (along with or in lieu of removing biopsy materials). Signature peaks in spectroscopy signals (or improved image resolution attributed to the hyperpolarized 129Xe signal) can indicate the presence of cancer via the increased peak in the signal due to the increased blood (and the injected xenon""s solubility therewith). Of course, other contrast mechanisms like chemical shift, T2*, diffusion, T1, and the like, can also be employed to exploit the 129Xe NMR image or spectroscopic signal in the tumor.
In addition, the present invention preferably employs a reliable quantitative concentration and/or predictable injection quantity. This predictable concentration of polarized gas can provide more predictable and reliable signal intensity for the associated MRI image, which, in turn, makes the method clinically useful as well as easier to correlate, patient to patient, or in a single patient over time. Preferably, the injectable quantity is selected to correspond to the introduction (injection) site; the venous side can use increased quantities compared to the arterial side (the venous side injections preferably sized at about 100 cc""s or less while the arterial injections are typically sized at about 14-20 cc""s or less.
In addition, the gas is preferably injected in a manner which facilitates reduced size bubbles introduced or formed by the injecting of gas. Controlling one or more of bubble size based on its responsive parameters, the quantity of gas administered, and/or injection rate (release) (as well as the configuration of the nozzle or exit chamber) of the gas can assure that the gaseous delivery to vasculature is done in an effective manner.
In one embodiment, the in vivo introduction of a suitable surfactant temporally and spatially proximate to (preferably upstream) the actual injection of the gas (temporally before or concurrent to the gas injection) can facilitate the dissipation or decreased size of injected bubbles in the venous and/or arterial system (depending on the injection site).
Further, the present invention recognizes that in order to allow the injected xenon gas sufficient time to enter the pulmonary vasculature, the NMR scanning is preferably delayed a sufficient amount of time after injection to allow for same, typically about 5-10 seconds post-injection. On the upper time limit, the NMR scan is also preferably performed within about one minute post-injection (and preferably 30 seconds after injection) as the polarization level will decay to an undesirable level relatively shortly after introduction into the body. Of course, multiple serially successive quantities of administered injection doses can be administered during the imaging session for obtaining a plurality of sequential or multi-shot images.
The dispensing methods, containers, and other apparatus of the present invention are advantageously configured to facilitate a longer T1 for the polarized gas and, thus, to promote a single-bolus sized formulation with a predictable level of polarization in a hyperpolarized product. Further, the 129Xe injectable gas product can be delivered and formulated in a way which allows the gas to be analyzed to determine its polarization level prior to delivery to thereby confirm the efficacy of the product just prior to (or in a preferred temporally appropriate point prior to) introduction into the patient.
Further, the present invention provides methods for sizing the length of a capillary stem on a container having a primary hyperpolarized gas holding chamber with a volume, the capillary stem having a volume which is substantially less than that of the gas holding chamber and includes a wall defining a flow channel aperture having a radius or width and a length. The wall has a gas-contacting surface formed of a material having a relaxivity value for a selected hyperpolarized gas associated therewith. The method comprises the steps of defining a capillary stem aperture size; establishing a relaxivity value for the material forming the capillary wall; and calculating an optimal capillary stem length. Similarly, the present invention can configure containers with capillary lengths chosen to increase the polarized life of the gas held therein.